Programmed necrosis is a regulated form of cell death directed by the kinases RIP1 and RIP3. A number of cell stress and host defense pathways prime cells for this programmed necrosis, and in the context of viral infection, elimination of infected cells benefits the host; however, when dysregulated necrosis promotes inflammation and potentially drives a range of disease states. At present, the signaling networks control by RIP1 and RIP3 kinases remain unclear. The NIH Director's Early Independence Award will enable me to establish a research program to define the molecular basis of necrosis. To generate a comprehensive picture, we will (1) characterize the signal transduction pathways upstream and downstream of RIP1 and RIP3, (2) identify new signaling components, (3) develop strategies for therapeutic intervention, and (4) extend these finding to genetic mouse models of inflammation caused by excessive cell death. These studies will contribute to our ability to treat disease through suppressing or altering cell death modalities.